59. Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination

Kassandra Sedillo, Flora Fan, Robert R. Knowles, Abigail G. Doyle

J. Am. Chem. Soc. 2024, 146, 20349–20356. DOI: 10.1021/jacs.4c05881

https://pubs.acs.org/doi/10.1021/jacs.4c05881

Abstract: Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N–H azoles with unactivated olefins remains an unsolved problem in synthesis. We report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N–H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N–H bond activation is proposed to proceed via polar addition of the N–H azole to a phosphine radical cation, followed by P–N α-scission from a phosphoranyl radical intermediate. Reactivity and N-site selectivity are classified by azole N–H BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.